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To the best of our knowledge, this is the first case of pregnancy with a healthy baby after treatment with an oral gonadotropin-releasing hormone (GnRH) antagonist in women with premature ovarian insufficiency. A 36-year-old female presented at our hospital after being diagnosed with premature ovarian insufficiency by a previous doctor. We administered clomiphene, human menopausal gonadotropin (hMG), and GnRH antagonist (injection) together with estrogen replacement for 11 cycles (27 months), but no follicular development was observed. When the oral GnRH antagonist (relugolix), which has recently become available, was used in the 12th cycle, follicular growth of 13 mm was confirmed on the 14th day of stimulation. After stimulation, the use of hMG and GnRH antagonist (injection) was continued, and a maturation trigger, human chorionic gonadotropin 10000 IU, was administered. Oocyte retrieval was performed successfully, intracytoplasmic sperm injection and frozen embryo transfer were performed, and fetal heartbeat was confirmed. The patient was admitted to the perinatal management facility. She delivered a healthy baby of 3,732 g via cesarean section at 41 weeks +2. This case shows the possibility of using an oral GnRH antagonist as an option for infertility treatment.
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Hormona Liberadora de Gonadotropina , Insuficiencia Ovárica Primaria , Humanos , Femenino , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Adulto , Embarazo , Administración Oral , Antagonistas de Hormonas/uso terapéutico , Antagonistas de Hormonas/administración & dosificación , Inducción de la Ovulación/métodosRESUMEN
Photochemical multi-component coupling reactions initiated by the activation of glycosyl bromides in the presence of 1,4-bis(diphenylamino)benzene (BDB) as an organic photocatalyst were developed. C-glycosides accompanied by olefin (di)functionalization were obtained. This method allows us to access various C-glycosides with alkene, carbonyl, alcohol, ether, and amide functionalities.
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In the intricate orchestration of the central dogma, pre-mRNA splicing plays a crucial role in the post-transcriptional process that transforms DNA into mature mRNA. Widely acknowledged as a pivotal RNA processing step, it significantly influences gene expression and alters the functionality of gene product proteins. Although U2-dependent spliceosomes efficiently manage the removal of over 99% of introns, a distinct subset of essential genes undergo splicing with a different intron type, denoted as minor introns, using U12-dependent spliceosomes. Mutations in spliceosome component genes are now recognized as prevalent genetic abnormalities in cancer patients, especially those with hematologic malignancies. Despite the relative rarity of minor introns, genes containing them are evolutionarily conserved and play crucial roles in functions such as the RAS-MAPK pathway. Disruptions in U12-type minor intron splicing caused by mutations in snRNA or its regulatory components significantly contribute to cancer progression. Notably, recurrent mutations associated with myelodysplastic syndrome (MDS) in the minor spliceosome component ZRSR2 underscore its significance. Examination of ZRSR2-mutated MDS cells has revealed that only a subset of minor spliceosome-dependent genes, such as LZTR1, consistently exhibit missplicing. Recent technological advancements have uncovered insights into minor introns, raising inquiries beyond current understanding. This review comprehensively explores the importance of minor intron regulation, the molecular implications of minor (U12-type) spliceosomal mutations and cis-regulatory regions, and the evolutionary progress of studies on minor, aiming to provide a sophisticated understanding of their intricate role in cancer biology.
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Neoplasias Hematológicas , Síndromes Mielodisplásicos , Humanos , Intrones , Empalmosomas/genética , Empalmosomas/metabolismo , Empalme del ARN , ARN Mensajero/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Factores de Transcripción/genéticaRESUMEN
Purpose: To analyze whether response to the GnRH test is a predictor of empty follicle syndrome (EFS) and to analyze independent risk factors for EFS. Methods: The GnRH test results of 3765 patients from 2016 to 2018 were used to define the reference range of the GnRH test. Risk factors for EFS were estimated by multivariate logistic analysis of 5282 cycles (5247 oocyte-retrieved cycles with GnRH agonist trigger and 35 cycles of EFS) conducted from 2016 to 2019. Results: GnRH testing showed basal hormone values as follows: median LH 5.2 (95 percentile; 1.3-12.6) mIU/mL, LH 30 min 22.0 (6.8-57.1), basal FSH 7.3 (3.0-20.5), FSH 30 min 11.5 (5.1-30.4) and FSH/LH ratio 1.5 (0.6-4.1). Independent risk factors for EFS were antral follicle count (adjusted odds ratio; 0.94, 95% CI; 0.89-0.99), basal LH (0.78, 0.66-0.90), and days duration of ovarian stimulation (1.41, 1.21-1. 60). The respective thresholds were 8 for AFC, 5.0 for basal LH, and 16 days for duration. Conclusions: LH 30 min values of the GnRH test did not predict EFS. Independent risk factors for EFS were AFC, basal LH and days duration of ovarian stimulation.
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ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.
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Cromatina , Factores de Transcripción , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ensamble y Desensamble de Cromatina , Diferenciación Celular , Células Madre Hematopoyéticas/metabolismoRESUMEN
The process of RNA splicing plays a pivotal role in gene expression and genetic information modification by converting pre-mRNA into mature mRNA. Dysregulation of this process has been associated with aberrant gene expression and function, leading to hematopoietic malignancies. Through recent clinical and mouse model analyses, insights have been gained into the mechanisms underlying splicing factor mutations that aid in myelodysplastic syndrome and acute myeloid leukemia. These mutations affect genes that modulate diverse cellular processes, including chromatin regulation, transcription factors, proliferation signaling, and inflammation pathway. The relationship between aberrant splicing and cancer remains unclear despite progress in understanding the functional consequences of splicing factor mutations. This review focuses on the mechanisms of disease development because of splicing factor mutations and their potential mechanism-based therapeutic applications.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Animales , Ratones , Empalme del ARN/genética , Factores de Empalme de ARN/genética , Neoplasias Hematológicas/genética , Síndromes Mielodisplásicos/terapia , Leucemia Mieloide Aguda/genética , MutaciónRESUMEN
Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.
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Leucemia Mieloide Aguda , Receptores de IgG , Humanos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Superficie , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Ribonucleoproteínas Nucleares Pequeñas , Microambiente TumoralRESUMEN
SETBP1 is a potential epigenetic regulator whose hotspot mutations preventing proteasomal degradation are recurrently detected in myeloid malignancies with poor prognosis. It is believed that the mutant SETBP1 exerts amplified effects of wild-type SETBP1 rather than neomorphic functions. This indicates that dysregulated quantitative control of SETBP1 would result in the transformation of hematopoietic cells. However, little is known about the roles of endogenous SETBP1 in malignant and normal hematopoiesis. Thus, we integrated the analyses of primary AML and healthy samples, cancer cell lines, and a newly generated murine model, Vav1-iCre;Setbp1fl/fl. Despite the expression in long-term hematopoietic stem cells, SETBP1 depletion in normal hematopoiesis minimally alters self-renewal, differentiation, or reconstitution in vivo. Indeed, its loss does not profoundly alter transcription or chromatin accessibilities. Furthermore, although AML with high SETBP1 mRNA is associated with genetic and clinical characteristics for dismal outcomes, SETBP1 is dispensable for the development or maintenance of AML. Contrary to the evidence that SETBP1 mutations are restricted to myeloid malignancies, dependency on SETBP1 mRNA expression is not observed in AML. These unexpected results shed light on the unrecognized idea that a physiologically nonessential gene can act as an oncogene when the machinery of protein degradation is damaged.
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Hematopoyesis , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Proteínas Portadoras/genética , Diferenciación Celular , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide Aguda/patología , Mutación , Proteínas Nucleares/genéticaRESUMEN
Hematopoiesis is maintained and regulated by a bone marrow-specific microenvironment called a niche. In hematological malignancies, tumor cells induce niche remodeling, and the reconstructed niche is closely linked to disease pathogenesis. Recent studies have suggested that extracellular vesicles (EVs) secreted from tumor cells play a principal role in niche remodeling in hematological malignancies. Although EVs are emerging as potential therapeutic targets, the underlying mechanism of action remains unclear, and selective inhibition remains a challenge. This review summarizes remodeling of the bone marrow microenvironment in hematological malignancies and its contribution to pathogenesis, as well as roles of tumor-derived EVs, and provides a perspective on future research in this field.
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Vesículas Extracelulares , Neoplasias Hematológicas , Trastornos Mieloproliferativos , Humanos , Médula Ósea/patología , Vesículas Extracelulares/patología , Trastornos Mieloproliferativos/patología , Neoplasias Hematológicas/patología , Hematopoyesis , Microambiente TumoralRESUMEN
Acquired sideroblastic anemia, characterized by bone marrow ring sideroblasts (RS), is predominantly associated with myelodysplastic syndrome (MDS). Although somatic mutations in splicing factor 3b subunit 1 (SF3B1), which is involved in the RNA splicing machinery, are frequently found in MDS-RS, the detailed mechanism contributing to RS formation is unknown. To explore the mechanism, we established human umbilical cord blood-derived erythroid progenitor-2 (HUDEP-2) cells stably expressing SF3B1K700E. SF3B1K700E expressing cells showed higher proportion of RS than the control cells along with erythroid differentiation, indicating the direct contribution of mutant SF3B1 expression in erythroblasts to RS formation. In SF3B1K700E expressing cells, ABCB7 and ALAS2, known causative genes for congenital sideroblastic anemia, were downregulated. Additionally, mis-splicing of ABCB7 was observed in SF3B1K700E expressing cells. ABCB7-knockdown HUDEP-2 cells revealed an increased frequency of RS formation along with erythroid differentiation, demonstrating the direct molecular link between ABCB7 defects and RS formation. ALAS2 protein levels were obviously decreased in ABCB7-knockdown cells, indicating decreased ALAS2 translation owing to impaired Fe-S cluster export by ABCB7 defects. Finally, RNA-seq analysis of MDS clinical samples demonstrated decreased expression of ABCB7 by the SF3B1 mutation. Our findings contribute to the elucidation of the complex mechanisms of RS formation in MDS-RS.
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Anemia Sideroblástica , Síndromes Mielodisplásicos , Fosfoproteínas , Factores de Empalme de ARN , 5-Aminolevulinato Sintetasa , Anemia Sideroblástica/genética , Humanos , Mutación , Síndromes Mielodisplásicos/genética , Fosfoproteínas/genética , Factores de Empalme de ARN/genéticaRESUMEN
Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation. SIGNIFICANCE: Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia. This article is highlighted in the In This Issue feature, p. 2221.
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Leucemia , Proteínas ras , Proteínas Cullin/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Leucemia/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteolisis , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/genética , Proteínas ras/genéticaRESUMEN
Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
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Leucemia Mieloide Aguda , Proto-Oncogenes , Animales , Inversión Cromosómica , Cromosomas Humanos Par 3/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Leucemia Mieloide Aguda/patología , Proteína del Locus del Complejo MDS1 y EV11/genética , Ratones , Proto-Oncogenes/genética , Factores de Transcripción/metabolismoRESUMEN
Pre-mRNA splicing is now widely recognized as a cotranscriptional and post-transcriptional mechanism essential for regulating gene expression and modifying gene product function. Mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are now considered among the most recurrent genetic abnormalities in patients with cancer, particularly hematologic malignancies. These include mutations in the major (U2-type) and minor (U12-type) spliceosomes, which remove >99% and ~0.35% of introns, respectively. Growing evidence indicates that aberrant splicing of evolutionarily conserved U12-type minor introns plays a crucial role in cancer as the minor spliceosome component, ZRSR2, is subject to recurrent, leukemia-associated mutations, and intronic mutations have been shown to disrupt the splicing of minor introns. Here, we review the importance of minor intron regulation, the molecular effects of the minor (U12-type) spliceosomal mutations and cis-regulatory regions, and the development of minor intron studies for better understanding of cancer biology.
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Neoplasias , Empalme del ARN , Humanos , Intrones/genética , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Empalme del ARN/genética , Empalmosomas/genética , Empalmosomas/metabolismoRESUMEN
Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies implicating mesenchymal stromal or stem cells (MSCs), a principal component of the HSC niche, in the inhibition of normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. Here, we demonstrate that both human and mouse MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Enforced MSC differentiation rescues the suppressed normal hematopoiesis in both in vivo and in vitro MDS models. Intriguingly, the suppression effect is reversible and mediated by extracellular vesicles (EVs) derived from MDS cells. These findings shed light on the novel MDS EV-MSC axis in ineffective hematopoiesis.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Síndromes Mielodisplásicos , Animales , Vesículas Extracelulares/metabolismo , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , Síndromes Mielodisplásicos/metabolismoRESUMEN
The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
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Antineoplásicos/farmacología , Azacitidina/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas Represoras/genética , Sulfonamidas/farmacología , Línea Celular Tumoral , Epigénesis Genética/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Mutación/efectos de los fármacos , Mutación Puntual/efectos de los fármacosRESUMEN
Myelodysplastic syndrome (MDS) is a group of hematopoietic disorders with limited treatment options. Anemia is a common symptom in MDS, and although erythropoiesis-stimulating agents such as erythropoietin, lenalidomide, and luspatercept are available to treat anemia, many MDS patients do not respond to these first-line therapies. Therefore, alternative drug development strategies are needed to improve therapeutic efficacy. Splicing modulators to correct splicing-related defects have shown promising results in clinical trials. Targeting differentiation of early erythroid progenitors to increase the erythroid output in MDS is another novel approach, which has shown encouraging results at the pre-clinical stage. Together, these therapeutic strategies provide new avenues to target MDS symptoms untreatable previously.
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Anemia , Síndromes Mielodisplásicos , Anemia/tratamiento farmacológico , Anemia/etiología , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológicoRESUMEN
Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.
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Predisposición Genética a la Enfermedad , Enfermedades Hematológicas/genética , Intrones/genética , Neoplasias/genética , Animales , Secuencia de Bases , Sistemas CRISPR-Cas/genética , Autorrenovación de las Células , Transformación Celular Neoplásica/patología , Células Clonales , Femenino , Genoma Humano , Enfermedades Hematológicas/patología , Células Madre Hematopoyéticas/metabolismo , Humanos , Masculino , Ratones Noqueados , Síndrome de Noonan/genética , Linaje , ARN/metabolismo , Empalme del ARN/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Bazo/patología , Factores de Transcripción/genéticaRESUMEN
Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
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Envejecimiento/genética , Hematopoyesis Clonal/genética , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Proteínas Represoras/genética , Serina-Treonina Quinasas TOR/metabolismo , Anciano , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Apoptosis/genética , Ciclo Celular/genética , Proliferación Celular/genética , Células Cultivadas , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Técnicas de Sustitución del Gen , Hematopoyesis/fisiología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/fisiología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Ratones , Ratones Transgénicos , Mutación , Proteínas Proto-Oncogénicas c-akt/metabolismo , RNA-Seq , Especies Reactivas de Oxígeno/farmacología , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sirolimus/farmacología , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación/efectos de los fármacos , Ubiquitinación/genéticaRESUMEN
In the gonadotropin-releasing hormone (GnRH) antagonist protocol, it is necessary to reinforce contraceptive guidance assuming that luteinizing hormone surge is not detected by measurement of serum level and ovulation is not suppressed by GnRH antagonist.
RESUMEN
Splicing factor 3b subunit 1 (SF3B1) is the most commonly mutated RNA splicing factor identified in myelodysplastic syndrome (MDS), chronic lymphocytic leukemia, and uveal melanoma. The mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer RNA sequencing to identify mutant SF3B1-dependent aberrant splicing events with a positive CRISPR screen to prioritize alterations that functionally promote oncogenesis. Our results indicated that diverse, recurrent SF3B1 mutations converge on the repression of bromodomain containing 9 (BRD9), a core component of the recently described non-canonical barrier-to-autointegration factor complex (ncBAF). Mutant SF3B1 recognizes intronic sequences within BRD9 as exons, thereby permitting inclusion of aberrant sequence (i.e., poison exon) that will result in the degradation of BRD9 mRNA. BRD9 depletion results in significant loss of ncBAF at CCCTC-binding factor (CTCF)-binding loci but has no impact on the localization of canonical BAF. These actions resulted in disturbed myeloid/erythroid differentiation and promoted the development of MDS and melanoma. Of note, correcting BRD9 mis-splicing in SF3B1-mutant cells with antisense oligonucleotides (ASOs), by targeting the poison exon with CRISPR-directed mutagenesis, or via the use of spliceosomal inhibitors are all potential therapeutic options. Our results implicate disruption of ncBAF as a critical factor promoting the development of the diverse array of cancers that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.